Stereoselective C  C Bond‐Forming Reactions Through C ( sp 3 ) H Bond Insertion of Metal Carbenoids

The selective and efficient construction of complex molecules is one of the most challenging goals in organic synthesis. To access such intriguing molecules, innovative methodologies in bond formation are required compared to traditional functional group transformations. It is for this reason that selective functionalization of the ubiquitous but inert C—H bond is of great interest to the chemical community [1–4]. A challenging aspect in organic chemistry for decades has been the stereoselective carbon–carbon bond formation by activation of a C(sp3)—H bond in the synthesis of pharmaceuticals, natural products, and other industrially relevant targets. A powerful approach to achieve such useful C–H functionalization is via C(sp3)–H insertion by metal carbenoids [5–8]. Generation of the metal carbenoid can occur through a number of precursors such as diazo compounds, ylide derivatives, hydrazones, and, more recently, triazoles. In this chapter, we will exclusively discuss metal carbenoids derived from α-diazocarbonyl compounds. In order to take advantage of metal carbenoid-induced C–H insertion, one must consider the reactivity of the electrophilic metal carbenoid. The synthetic utility of the free carbenes is limited by low selectivity in most reactions. In contrast, when nitrogen extrusion is facilitated by a transition metal, the resulting metal carbenoid retains the reaction scope of a free carbene while allowing highly selective transformations to occur (Figure 1.1). Historically, copper was used as the transition metal source, but few examples of efficient and selective C–H insertion were reported. The key development in C–H insertion was the discovery by the Teyssié group that dirhodium(II) carboxylates catalyzed the intermolecular C–H insertion reaction of ethyl diazoacetate with alkanes [9]. Following this, Wenkert et al. [10] and Taber and Petty [11] highlighted the potential of intramolecular C–H insertion reactions of α-diazocarbonyl compounds to lead to cyclopentanone derivatives. Importantly, it was demonstrated that C–H insertion takes place with retention of